Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Angew Chem Int Ed Engl. 2022 Sep 26;61(39):e202206277. doi: 10.1002/anie.202206277. Epub 2022 Aug 25.
Ferroptosis is a new form of regulated, non-apoptotic cell death driven by iron-dependent phospholipid peroxidation. Its therapeutic potential is however, greatly limited by the low efficiency of regulating cell ferroptosis in vivo. Herein, we report a PROTAC-based protein degrader that depletes endogenous glutathione peroxidase 4 (GPX4) and induces cancer cell ferroptosis. We demonstrate that a rationally designed GPX4 degrader, dGPX4, can deplete tumor cell GPX4 via proteasomal protein degradation, showing a five-fold enhancement of ferroptosis induction efficiency compared to that of GPX4 inhibition using ML162. Moreover, we show that the intracellular delivery of dGPX4 using biodegradable lipid nanoparticles (dGPX4@401-TK-12) induces cell-selective ferroptosis by targeting cancer cell microenvironment. The in vivo administration of dGPX4@401-TK-12 effectively suppresses tumor growth without appreciable side effects. We anticipate the protein degradation strategy described herein could be easily expanded to other essential regulatory proteins of ferroptosis for developing targeted cancer therapeutics.
铁死亡是一种新的受调控的非细胞凋亡性细胞死亡形式，由铁依赖性磷脂过氧化所驱动。然而，其治疗潜力受到体内调节细胞铁死亡效率低下的极大限制。在此，我们报告了一种基于 PROTAC 的蛋白降解剂，它可以耗尽内源性谷胱甘肽过氧化物酶 4（GPX4）并诱导癌细胞铁死亡。我们证明，一种合理设计的 GPX4 降解剂 dGPX4 可以通过蛋白酶体蛋白降解耗尽肿瘤细胞中的 GPX4，与使用 ML162 抑制 GPX4 相比，铁死亡诱导效率提高了五倍。此外，我们表明，使用可生物降解的脂质纳米粒（dGPX4@401-TK-12）将 dGPX4 递送到细胞内可以通过靶向癌细胞微环境来诱导细胞选择性铁死亡。体内给予 dGPX4@401-TK-12 可有效抑制肿瘤生长，而没有明显的副作用。我们预计，本文所述的蛋白降解策略可以很容易地扩展到铁死亡的其他必需调节蛋白，以开发靶向癌症治疗药物。
